Several publications and patent are referenced in this application by author name and year of publication in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications and patent documents is incorporated by reference herein.
Ataxia telangiectasia (AT) is an autosomal recessive disease caused by mutations in the gene, ataxia telangiectasia mutated (ATM), on human chromosome 11q21 (Savitsky et al, 1995). The ATM product is a protein kinase that plays a role in DNA damage repair through cell cycle regulation. AT is a rare disease, with a frequency of approximately 1/40,000 individuals. The corresponding frequency of heterozygous carriers is about 1/100. Although AT is a recessive disease, epidemiological studies have shown that AT carriers have shortened lifespans and elevated risks for cancer, especially breast cancer. Cellular studies have also shown that heterozygous carriers of AT have an increased sensitivity to ionizing irradiation (IR) (Swift et al, 1986; Swift et al, 1991; Athma et al, 1996; Broeks et al, 2000). Some reports have estimated that AT carriers have a 5-fold increase in risk for breast cancer compared to normal controls and may account for 8–18% of all breast cancer patients in the United States (Swift et al, 1976).
Despite the importance of detecting AT carriers, there is no precise diagnostic assay for identifying them. ATM is a large gene (approximately 150 kb) and has no common mutations which makes it difficult to design sequence-based diagnostic methods for identifying carriers of AT (Gilad et al, 1996; Wright et al, 1996; Concannon & Gatti, 1997). In addition, existing protein and cell-based assays are inaccurate for identifying heterozygous carriers, and are also time- and labor-intensive (Telatar et al, 1996). Nevertheless, a reliable method for identifying AT carriers will make it possible to establish the risk of radiation-induced cancer and to develop safety guidelines for radiation-based diagnostic procedures and therapies.